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Xianlin Zou's Dissertation Defense (5/6/2021) : Interlocking Mechanisms Regulating the Circadian Clock Response to DNA Damage

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Xianlin Zou

Dissertation Defense: Interlocking Mechanisms Regulating the Circadian Clock Response to DNA Damage

Xianlin Zou

Graduate Student, Department of Biological Sciences, College of Science
David W. Francis and Lillian Francis Memorial Scholar, Finkielstein Lab, Fralin Biomedical Research Institute at VTC

May 6, 2021 at 1:00 p.m.

About this Dissertation

The circadian clock relies on post-translational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat–containing proteins (β-TrCPs), which are F-box–containing proteins that function as substrate recognition subunits of the SCFβ-TRCP ubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. Zou, working in the lab of Carla Finkielstein, Ph.D., identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Zou's results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis.

Committee Members

Mentor

Carla Finkielstein, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC

Committee Members

  • Sarah Clinton, Ph.D., Associate Professor and Associate Director, School of Neuroscience, College of Science, Virginia Tech
  • Shihoko Kojima, Ph.D., Assistant Professor of Biological Sciences, Department of Biological Sciences, College of Science, Virginia Tech
  • Peter Kennelly, Ph.D., Professor, Department of Biochemistry, College of Agriculture and Life Sciences, Virginia Tech
  • Jing Chen, Ph.D., Assistant Professor of Biological Sciences, Department of Biological Sciences, College of Science, Virginia Tech